Summary: For the foreseeable future, bioprosthetic heart valves (BHV) fabricated from xenograft biomaterials will remain the dominant replacement prosthetic valve design. However, BHV durability remains limited to 10-15 years. Failure is usually the result of leaflet tructural deterioration mediated by fatigue and/or tissue mineralization. Thus, independent of valve design specifics (e.g. standard stented valve, percutaneous delivery), the development of novel xenograft biomaterials with improved durability remains an important clinical goal. This represents a unique cardiovascular engineering challenge resulting from the extreme valvular mechanical demands that occur with blood contact. Yet, current BHV assessment relies exclusively on device-level evaluations, which are confounded by simultaneous and highly coupled biomaterial mechanical behaviors and fatigue, valve design, hemodynamics, and calcification. Thus, despite decades of clinical BHV usage and growing popularity, there exists no acceptable method for assessing and simulating BHV durability at the component biomaterial level. This situation has contributed to the current stagnation in BHV biomaterial development, limiting rationally developed improvements in BHV durability. We hypothesize that a biomechanically rigorous and physiologically realistic in-vivo approach can be developed for a mechanistic understanding of intrinsic BHV biomaterial performance. Once developed, such an approach can be used to rationally design novel biomaterials that significantly improve BHV durability. While calcification prevention has not been completely solved, ethanol post-treatment has been shown to strongly reduce its onset. Moreover, others and we have shown that tissue degeneration is a major independent mechanism underlying BHV limited durability both in-vitro and in-vivo. Thus, our focus will be on mechanisms of early tissue degeneration and means to reduce damage accumulation, leading to improving BHV durability.